Introduction The objective of this pilot randomized controlled trial was to investigate the combined effect of a Mediterranean diet and naltrexone/bupropion treatment on body weight, metabolic parameters, and quality of life in overweight or obese breast cancer survivors. Methods Forty-four breast cancer survivors were randomly assigned to receive the Mediterranean diet plus naltrexone/bupropion medication (breast cancer survivor MeDiet+NB group) or the Mediterranean diet alone (breast cancer survivor MeDiet-only group). Twenty-eight age-matched non-cancer patients were instructed to consume the Mediterranean diet plus naltrexone/bupropion medication (non-cancer MeDiet+NB group). After the 8-week intervention, changes in body weight, metabolic parameters, nutrient intake, and quality of life of the three groups were assessed. Results Significant weight loss of 2.8 kg was noted for the breast cancer survivor MeDiet+NB group, 1.8 kg for the breast cancer survivor MeDiet-only group, and 2.5 kg for the non-cancer MeDiet+NB group after 8 weeks ( P < 0.05 versus baseline by Wilcoxon’s signed-rank test). All three groups also exhibited significantly lower fasting glucose, insulin, and homeostasis model assessment of insulin resistance levels ( P < 0.05). Quality of life as assessed by self-reported questionnaires showed improvement in all participants ( P < 0.05). However, there were no significant differences of changes in body weights, metabolic parameters, and quality of life among the three groups or between the MeDiet+NB and MeDiet-only groups. Conclusion We found that the Mediterranean diet, with or without naltrexone/bupropion treatment, facilitates weight loss, improves metabolic parameters, and increases quality of life. The combination of the Mediterranean diet with naltrexone/bupropion treatment did not produce superior changes when compared to the Mediterranean diet alone. Trial Registration This trial was retrospectively registered on 10 July 2018 as NCT03581630 at ClinicalTrials.gov ( https://clinicaltrials.gov/ct2/show/NCT03581630 ).